The goals of this competing renewal are to illuminate the long-term relationships among overall diet quality, energy balance, weight gain, and cardiovascular disease (CVD) risk in the Nurses' Health Study (NHS), NHS II, and Health Professionals Follow-up Study (HPFS). Our proposal includes several specific aims. First, we will evaluate the long-term relationship between changes in diet quality indices (such as the alternate Healthy Eating Index [aHEI], alternate Mediterranean Diet [aMED], Dietary Approaches to Stop Hypertension [DASH], Food Quality Score [FQS]) and weight gain in over 120,000 participants in the NHS, NHS II, and HPFS. We will test the hypothesis that higher diet quality is inversely associated with long-term weight gain. Second, we will explore biological pathways that may mediate the effects of diet quality on weight change. In particular, we will evaluate the inter-relationships among diet quality, total energy intake (measured by doubly-labeled water [DLW]), physical activity (measured by accelerometers), sleep duration, and body weight in a subsample of NHS/HPFS participants (n=1,300) enrolled in the ongoing Lifestyle Validation Study (LVS). We hypothesize that the inverse association between diet quality and body mass index (BMI) is at least partially explained by lower energy intake. We will also evaluate the long-term relationships between change in diet quality and changes in biomarkers of the brain-adipose axis (leptin, soluble leptin receptor (sOB-R), insulin, adiponectin, retinol binding protein 4 [RBP4], tumor necrosis factor receptor 2 [TNF-R2], and interleukin 6 [IL-6]) among 1,000 healthy NHS II participants who provided repeated fasting bloods in 1996/1997 and 2011/2012. Furthermore, we will examine whether diet quality modifies the associations between genetic variants and BMI and waist-to-hip ratio (WHR). These analyses will be conducted among about 13,000 men and women in the NHS and HPFS with existing genome-wide association study (GWAS) data. We hypothesize that higher diet quality attenuates a genetic predisposition to a higher BMI and WHR. Finally, we will evaluate the role of weight change in mediating the relationship between improvement in the diet quality indices and subsequent lower risk of coronary heart disease (CHD) and stroke among over 100,000 men and women in the NHS and HPFS. We hypothesize that the inverse association between improved diet quality and subsequent risk of CHD and stroke is partly mediated through less weight gain during follow-up. This competing renewal builds upon our long-standing work on dietary pattern analysis and CVD risk and extends to novel areas of diet quality, energy balance, and novel biomarkers in the brain-adipose axis. This proposal is highly cost-effective because it utilizes existing uniquely rich data resources with repeated blood samples and objective measurements of total energy intake and physical activity and requests funds only for biomarker measurements and proposed data analysis.